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Regulation of Hepatic Gluconeogenesis by an ER-Bound Transcription Factor, CREBH

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.
Cell metabolism (Impact Factor: 16.75). 04/2010; 11(4):331-9. DOI: 10.1016/j.cmet.2010.02.016
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ABSTRACT Endoplasmic reticulum (ER)-bound transcription factor families are shown to be involved in the control of various metabolic pathways. Here, we report a critical function of ER-bound transcription factor, CREBH, in the regulation of hepatic gluconeogenesis. Expression of CREBH is markedly induced by fasting or in the insulin-resistant state in rodents in a dexamethasone- and PGC-1alpha-dependent manner, which results in the accumulation of active nuclear form of CREBH (CREBH-N). Overexpression of constitutively active CREBH activates transcription of PEPCK-C or G6Pase by binding to its enhancer site that is distinct from the well-characterized CREB/CRTC2 regulatory sequences in vivo. Of interest, knockdown of CREBH in liver significantly reduces blood glucose levels without altering expression of genes involved in the ER stress signaling cascades in mice. These data suggest a crucial role for CREBH in the regulation of hepatic glucose metabolism in mammals.

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    • "The data also allowed us to conclude that during fasting, only a small quantity of pyruvate is directed toward the generation of GLY-TAG (1/20 to glucose) in the liver of both the C and LPHC animals. Other studies (Cassuto et al. 2005; Hall et al. 2007; Lee et al. 2010) have indicated that corticosterone, a glucocorticoid hormone found in high levels in the blood of LPHC animals (Dos Santos et al. 2012), inhibits the transcription of the PEPCK gene in adipose tissue but stimulates it in the liver and renal cortex (Meisner et al. Fig. 4. Protein levels of PEPCK and GyK in the livers of fasted rats (15 h) previously fed a control diet (C) or a low-protein, high-carbohydrate diet (LPHC) for 15 days. "
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    ABSTRACT: The our objective was to investigate the adaptations induced by a low-protein, high-carbohydrate (LPHC) diet in growing rats, which by comparison with the rats fed a control (C) diet at displayed lower fasting glycemia and similar fasting insulinemia, despite impairment in insulin signaling in adipose tissues. In the insulin tolerance test the LPHC rats showed higher rates of glucose disappearance (30%) and higher tolerance to overload of glucose than C rats. The glucose uptake by the soleus muscle, evaluated in vivo by administration of 2-deoxy-[(14)C]glucose, increased by 81%. The phosphoenolpyruvate carboxykinase content and the incorporation of [1-(14)C]pyruvate into glucose was also higher in the slices of liver from the LPHC rats than in those from C rats. The LPHC rats showed increases in l-lactate as well as in other gluconeogenic precursors in the blood. These rats also had a higher hepatic production of glucose, evaluated by in situ perfusion. The data obtained indicate that the main substrates for gluconeogenesis in the LPHC rats are l-lactate and glycerol. Thus, we concluded that the fasting glycemia in the LPHC animals was maintained mainly by increases in the hepatic gluconeogenesis from glycerol and l-lactate, compensating, at least in part, for the higher glucose uptake by the tissues.
    Canadian Journal of Physiology and Pharmacology 04/2014; DOI:10.1139/cjpp-2013-0346 · 1.55 Impact Factor
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    • "Therefore, CREBH can also contribute to the expansion of mRNA expression even during exposure to a conventional ER stressor. More recently, CREBH was shown to directly regulate genes involved in gluconeogenesis (Lee et al., 2010) and lipid metabolism (Zhang et al., 2012). The latter of these processes showed a stronger CREBH dependence in the context of a high-fat atherogenic diet, raising the question of the extent to which physiological stimuli such as obesity impact gene expression through the canonical UPR vs. through pathways that enlist the action of molecules like CREBH to produce a unique response. "
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    ABSTRACT: The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes.
    Frontiers in Genetics 12/2013; 4:256. DOI:10.3389/fgene.2013.00256
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    • "BioMed Research International response element (CREBHRE) in the target gene promoter to modulate transcription [10] [12]. Here, we report that a CREBHRE is located in the promoter of human APOA5, which is a critical region for the transcriptional regulation of the APAO5 gene by CREBH. "
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    ABSTRACT: The cyclic AMP response element-binding protein H (CREBH) plays important roles in hepatic lipogenesis, fatty acid oxidation, and lipolysis under metabolic stress. Here, we report CREBH as a novel regulator of human APOA5. Knockdown of endogenous CREBH expression via small interfering RNA resulted in the downregulation of human APOA5 mRNA expression in human hepatoma cells, HepG2. Sequence analysis suggested that putative CREBH response element (CREBHRE) is located in the human APOA5 promoter region and is highly conserved in both human and rodent. To clarify whether the human APOA5 promoter is regulated by CREBH, we analyzed the human APOA5 promoter region using a transient transfection assay and determined that transfection of CREBH induced human APOA5 promoter activity. Moreover, it was shown that CREBH directly regulated human APOA5 gene expression by binding to a unique CREBHRE located in the proximal human APOA5 promoter region, using 5'-deletion and mutagenesis of human APOA5 promoter analysis and chromatin immunoprecipitation assay. Taken together, our results demonstrated that human APOA5 is directly regulated by CREBH via CREBHRE and provided a new insight into the role of this liver-specific bZIP transcription factor in lipoprotein metabolism and triglyceride homeostasis.
    07/2013; 2013:892491. DOI:10.1155/2013/892491
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